Sevoflurane is produced by several known methods. A commonly used method involves the reaction of formaldehyde (or a formaldehyde equivalent), hydrogen fluoride (HF), and hexafluoroisopropanol (HFIP). U.S. Pat. No. 4,250,334 describes a process in which HFIP is added to a mixture of a stoichiometric excess of paraformaldehyde and HF plus sufficient sulfuric acid to sequester most of the water formed in the reaction. WO 97/25303 describes a process for the production of sevoflurane in which essentially pure bis(fluoromethyl)ether (BFME) is allowed to react with HFIP and sulfuric acid. U.S. Pat. No. 6,469,219 describes a process in which HFIP and a formaldehyde equivalent are allowed to react with excess HF under distillative or extractive conditions in order to produce sevoflurane. Other synthetic routes generate a different impurity profile, but still require a final distillation in order to produce a pharmaceutically acceptable form of sevoflurane.
In all of these processes, unreacted HFIP may remain in the product mixture, as well as BFME, methyl hexafluoroisopropyl ether (MHFIP), polyethers containing the HFIP and formaldehyde moieties, and various other undesired species. These impurities must be removed from the crude sevoflurane product in order to obtain a pharmaceutically acceptable form of the material.
Many of these impurities can be removed by distillation, but it has been disclosed in U.S. Pat. No. 5,684,211 that crude sevoflurane can decompose or disproportionate under distillative conditions and that the product could not be adequately purified as a result of this decomposition/disproportionation. For example, dehydrofluorination of sevoflurane may occur during distillation, leading to fluoromethyl 1,1,3,3,3-pentafluoroisopropenyl ether (also known as Compound A) as a new impurity. It is difficult to separate this decomposition/disproportionation product from sevoflurane by distillation because their boiling points are very similar.
This type of decomposition can be prevented by the use of a decomposition suppressive agent in the distillation process. Suppressive agents known in the art include hydroxides of alkali metals, hydrogenphosphates of alkali metals, phosphates of alkali metals, hydrogencarbonates of alkali metals, borates of alkali metals, sulfites of alkali metals, alkali metal salts of acetic acid, alkali metal salts of phthalic acid and boric acid. Potential drawbacks to the use of such agents, however, include added expense for their use and disposal, as well as the necessity to completely remove them from the drug product.
Furthermore, although fluoroethers are excellent anesthetic agents, some fluoroethers have been reported to encounter stability problems. More specifically, it has been reported (U.S. Pat. No. 5,990,176 and others) that certain fluoroethers, in the presence of one or more Lewis acids, degrade into several by-products including potentially toxic chemicals such as HF and/or HFIP. Hydrofluoric acid is toxic by ingestion and inhalation and is highly corrosive to skin and mucous membranes. Therefore, the degradation of fluoroethers to chemicals such as HF is of great concern to the medical community. In fact, quantities of Ultane® brand sevoflurane had to be recalled on two occasions due to potentially patient-threatening decomposition caused by exposure to Lewis acids.
The Lewis-acid induced decomposition of sevoflurane can be suppressed by the addition of certain Lewis-acid inhibitors to the product. Lewis-acid inhibitors include, but are not limited to, water, butylated hydroxytoluene, methylparaben, propofol, thymol, and propylparaben. The drawbacks of using such agents include the added expense and processing time for their incorporation into the drug product.
Thus, a distillative method is needed for the efficient separation of sevoflurane from impurities without further decomposition/disproportionation that does not require the use of any type of suppressive agent in order to achieve a substantially pure product. Also, this method should result in a product that does not decompose over long periods of time, thus eliminating the need for the addition of sevoflurane decomposition suppression agents.